Morgensztern, Daniel

Mesothelioma is a rare cancer that originates from the mesothelial surfaces of certain sites within the body. Pleural mesothelioma is the most common type and represents approximately 85% of mesotheliomas. The NCCN Guidelines for Mesothelioma: Pleural provide recommendations for evaluation and treatment in patients with pleural mesothelioma. The NCCN Guidelines will continue to be updated annually based on available clinical evidence and panel consensus.

Abstract Purpose: Circulating tumor fraction estimate (ctFE) is a machine learning–derived composite metric of circulating tumor DNA (ctDNA) burden. We hypothesized that pre-treatment and early on-treatment ctFE could robustly risk-stratify patients with locally advanced (LA) and oligometastatic non–small cell lung cancer (NSCLC) treated with radiotherapy (RT). Experimental Design: In a prospective phase II clinical trial (NCT03916419), 26 patients with unresectable stage IIB to IIIC NSCLC received magnetic resonance (MR)-guided hypofractionated chemoradiotherapy (chemoRT) followed by immunotherapy. Plasma ctDNA was profiled at baseline and mid-treatment (days 10–14) to derive ctFE and maximum variant allele frequency (Max VAF). A burden-based ctFE threshold derived from baseline samples was applied unchanged to mid-treatment samples and validated in two external cohorts: LA NSCLC treated with chemoRT (LA-RW; n = 94) and oligometastatic NSCLC treated with RT (OM-RW; n = 309). Results: Pre- and mid-treatment ctFE burden strongly stratified overall survival (OS) and progression-free survival (PFS), outperforming Max VAF and ctFE detectability. The baseline ctFE was prognostic for OS (HR 5.93, P = 0.005) and PFS (HR 11.08, P < 0.001) and remained significant at mid-treatment (OS: HR 7.08; PFS: HR 12.06; both P < 0.001). Early ctFE dynamics defined three molecular response groups with OS separation (median OS 60.8 vs. 13.0 vs. 2.9 months; P < 0.001). ctFE remained associated with survival in both validation cohorts. Conclusions: Early ctFE derived from a clinically available, tumor-naïve ctDNA assay enables noninvasive risk stratification in LA and oligometastatic NSCLC treated with RT, supporting its use as a practical biomarker for precision treatment adaptation.

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Non-Small Cell Lung Cancer (NSCLC) provide recommendations for the treatment of patients with NSCLC, including diagnosis, primary disease management, surveillance, and subsequent treatment. The panel has updated the list of recommended targeted therapies based on recent FDA approvals and clinical data. This selection from the NCCN Guidelines for NSCLC focuses on treatment recommendations for advanced or metastatic NSCLC with actionable biomarkers.

Abstract Background: Personalizing chemoradiotherapy (chemoRT) for locally advanced non-small cell lung cancer (LA-NSCLC) is limited by the lack of early biomarkers that inform response during treatment. Current circulating tumor DNA (ctDNA) molecular residual disease assays predict post-treatment outcomes but lack mid-treatment utility. ctDNA burden estimation has traditionally relied on variant-centric metrics such as maximum variant allele fraction (Max VAF), which rely on mutation-specific signals and may be confounded by histology-dependent shedding variability, allelic imbalance, and clonal hematopoiesis. Here we present circulating tumor fraction estimate (ctFE), a machine-learning composite score that integrates VAF distributions, copy-number alterations, and germline B-allele frequency deviations to approximate global tumor burden using a widely available, tumor-naïve clinical platform. Methods: A burden-based ctFE threshold was derived using pre-treatment plasma from a prospective phase II clinical trial of MR-guided hypofractionated chemoRT (LA-WU, n=26), locked, and applied unchanged to early mid-treatment samples (day 10-14). To test scalability and generalizability, its prognostic performance was validated in two real-world cohorts: 94 LA-NSCLC patients receiving definitive chemoRT (LA-RW) and 309 oligometastatic NSCLC patients receiving consolidative RT (OM-RW). ctFE and Max VAF were compared as continuous predictors across cohorts. Results: ctFE consistently outperformed Max VAF. In LA-WU, pre-treatment ctFE was associated with overall survival (OS HR=1.15, p=0.04) and progression-free survival (PFS HR=1.84, p=0.009), whereas Max VAF was not. Mid-treatment ctFE remained prognostic for PFS (HR=1.14, p=0.026). Early ctFE dynamics defined three molecular response groups with marked OS separation: consistently low, responder, and nonresponder groups (median OS 60.8 vs 13.0 vs 2.9 months, respectively; p<0.001). In multivariable models including both biomarkers, higher ctFE remained independently associated with worse survival in LA-RW (OS HR=1.88, p=0.010) and OM-RW (OS HR=1.37, p=0.040; PFS HR=1.45, p=0.008), whereas Max VAF did not. The locked ctFE threshold stratified OS across all cohorts (LA-WU HR=5.93; LA-RW HR=9.08; OM-RW HR=2.26; all p<0.001). Conclusion: ctFE provides clinically meaningful pre- and mid-treatment risk stratification and consistently outperforms Max VAF across locally advanced and oligometastatic NSCLC cohorts. We show that ctFE is a biologically informative, clinically generalizable and scalable ctDNA burden metric measurable using a tumor-naïve, off-the-shelf assay, supporting its practical utility in biomarker-adapted radiotherapy strategies. Citation Format: Ayesha Hashmi, Jessica Linford, Pradeep S. Chauhan, Kaushal Parikh, Rotem Ben-Shachar, John Guittar, Malvika Pillai, Jyoti Patel, Matteo Bergsagel, Nicholas P. Semenkovich, Kenneth R. Olivier, Sean S. Park, Dawn Owen, David M. Routman, Katie N. Lee, Alex D. Sherry, Aaron S. Mansfield, Daniel Morgensztern, Ramaswamy Govindan, Clifford G. Robinson, Carmen Bergom, Saiama N. Waqar, Bruna Pellini Ferreira, Gregory R. Vlacich, Aadel A. Chaudhuri. Early ctDNA quantification by ctFE outperforms Max VAF for survival stratification across locally advanced and oligometastatic NSCLC treated with radiotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 1183.

The NCCN Guidelines for Non–Small Cell Lung Cancer (NSCLC) provide recommendations for the treatment of NSCLC. These NCCN Guidelines Insights discuss recent updates to the NCCN Guidelines, with a focus on systemic therapy options for the treatment of patients with nonmetastatic NSCLC and the corresponding molecular testing considerations.

Thymomas and thymic carcinomas are rare mediastinal tumors that originate in the thymus. Patients with thymoma may experience symptoms associated with autoimmune paraneoplastic diseases (such as myasthenia gravis), which typically do not occur in patients with thymic carcinoma. The NCCN Guidelines for Thymomas and Thymic Carcinomas provide guidance for the diagnosis, treatment, and surveillance of patients with thymoma and thymic carcinoma. Involvement of a multidisciplinary team with experience treating thymomas and thymic carcinomas is highly recommended.

2558 Background: Clinical validation studies have shown that early dynamic changes in circulating tumor DNA (ctDNA) tumor fraction (TF) can predict clinical outcomes. Yet few studies have evaluated the clinical value of longitudinal monitoring throughout the course of treatment. Here we evaluate longitudinal changes in ctDNA TF and clinical outcomes in an advanced real-world pan-cancer cohort of patients (pts) treated with immune checkpoint inhibitors (ICIs). Methods: The cohort included deidentified pts from the Tempus clinicogenomic database with stage IIIB or IV solid tumors who underwent ctDNA NGS and were treated with an FDA-approved ICI +/- chemotherapy (CT). Pts had a pre-treatment baseline liquid biopsy (T0) and ≥1 on-treatment sample Ti within 21-180 days of ICI. xM for treatment response monitoring estimates TF via an ensemble algorithm that incorporates variant and copy number information. Response status was determined at each on-treatment timepoint Ti relative to T0. Pts were classified as a Molecular Responder (MR) if TF < 1% at T0 and Ti or if TF decreased by ≥ 50% from T0 to Ti; otherwise, they were classified as a Molecular Non-Responder (nMR). Pts with TF < 0.09% at T0 and Ti were classified as ctDNA not detected. The longitudinal cohort included pts with ≥2 on-treatment timepoints, further classified based on the most frequent classification across each Ti as longitudinal MR, longitudinal nMR and longitudinal ctDNA not detected. If no classification was dominant, the most recent classification was used. Real-world overall survival (rwOS) was defined from T1 to death and assessed by log-rank test. Results: The full cohort of 84 pts with > 10 solid tumors included 34.5% (n = 29) NSCLC and 16.7% (n = 14) SCLC. The majority of pts (59.5%, n = 50) received ICI+CT, (64.0% first-line [1L]), and 40.5% (n = 34) ICI-only (35.3% 1L). rwOS was longer for 53 MRs vs. 18 nMRs (median not reached vs. 7.0 months, P < 0.005); 13 pts had no ctDNA detected. The longitudinal subcohort of 35 pts was 31.4% (n = 11) NSCLC, 20.0% (n = 7) prostate cancer, and 14.3% (n = 5) SCLC; 45.7% (n = 16) ICI+CT (56.3% 1L), 54.3% (n = 19) ICI-only (31.6% 1L). On average, pts had 3 on-treatment liquid biopsies, with a median time between on-treatment samples of 91 days. Twelve pts were longitudinal nMRs (10 MR or ctDNA not detected at T1), 18 longitudinal MRs, and 5 longitudinal no ctDNA detected. There were 6 death events in the longitudinal nMRs, 3 in the longitudinal MRs (all > 18 months after T1), and no death events in the longitudinal no ctDNA detected group. Longitudinal MRs had longer rwOS than longitudinal nMRs (median 37.4 months vs 8.7 months, P < 0.005). Conclusions: Longitudinal nMR was associated with worse survival compared to longitudinal MR. Longitudinal, molecular biomarker dynamics may be a useful clinical treatment decision tool for monitoring treatment response to ICI therapy.

TPS8113 Background: There are currently three approved approaches for patients with resectable NSCLC including neoadjuvant chemoimmunotherapy, adjuvant chemoimmunotherapy and perioperative treatment with neoadjuvant chemoimmunotherapy followed by adjuvant immunotherapy. All regimens were approved after showing event-free survival (EFS) or disease-free survival (DFS) benefit with the addition of immunotherapy to chemotherapy compared to chemotherapy alone. Each approach has its benefits and risks. Starting immunotherapy prior to surgery may improve treatment compliance and efficacy of immunotherapy. Nevertheless, neoadjuvant chemoimmunotherapy may result in missing an opportunity for curative surgery and increase the complexity of tumor resection. PROSPECT-LUNG (NCT06632327) is a randomized study evaluating whether starting chemoimmunotherapy before or after surgery leads to better outcomes. Methods: This is a randomized phase 3 trial in which patients will be randomized 1:1 to surgery followed by chemoimmunotherapy (adjuvant arm) or neoadjuvant chemoimmunotherapy followed by surgery and adjuvant therapy (perioperative arm). Patients with histologic or cytologic confirmation of surgically resectable stage IIA-IIIB NSCLC (per AJCC 9th edition) or stage IIA to IIIB per AJCC 8 th edition up to single ipsilateral mediastinal station (N2a), ECOG PS ≤ 2 (or Karnofsky ≥ 60%), no prior treatment for NSCLC and no previous malignancy within 3 years are eligible. The dual primary endpoints are real-world event free survival (rwEFS) defined as date from randomization to date of the first of the following events: failure to undergo resection for any reason, progression prior to surgery that precludes resection, recurrence or progression at any time after surgery or death from any cause, and overall survival (OS) defined as time from randomization to death from any cause. The target accrual is 1,100 patients assuming one-sided type I error of 0.03 for OS endpoint and 0.02 for rwEFS endpoint. This sample size will enable the detection of a 3-year rwEFS improvement from 55% in the adjuvant therapy arm to 64% in the perioperative arm with an 84% power. This sample size would detect an HR of 0.73 (improvement in median OS from 8.1 to 11 years in favor of the perioperative arm, 5-year OS from 65% in the adjuvant arm to 73% in the perioperative arm, assuming exponential survival) with 83.6% power. The study has a pragmatic design with minimal data collection, reporting of adverse events that lead to discontinuation of therapy, hospitalization or death only. It allows providers to choose therapy per standard of care (FDA approved or on NCCN), includes patients with ECOG performance status 2, permits use of local laboratory testing and imaging studies and determination of recurrence/progression will be done by local treating physicians with no use of RECIST. Clinical trial information: NCT06632327 .

TPS3164 Background: TUB-030 is a novel antibody-drug conjugate (ADC) targeting 5T4, an oncofetal antigen expressed in various solid tumors with limited expression in healthy tissues. TUB-030 leverages optimized biophysical properties, an effector-silenced antibody, and an exatecan payload to maximize the therapeutic index and minimize off-target toxicities. Preclinical studies demonstrated potent anti-tumor activity, including long-lasting tumor regression at doses as low as 1 mg/kg and durable responses even in tumors with low 5T4 expression. Methods: 5-STAR 1-01 is a multicenter, first-in-human dose escalation and dose optimization Phase I/IIa clinical trial designed to investigate safety, tolerability, pharmacokinetics (PK), and efficacy of the anti-5T4 ADC TUB-030 in patients with advanced and metastatic solid tumors. Eligible patients have one of the following tumor types: head and neck squamous cell carcinomas (HNSCC), non-small-cell lung cancer (NSCLC), small cell lung cancer, pleural mesothelioma, triple-negative breast cancer, HR+/HER2- breast cancer, esophageal cancer, gastric cancer, pancreatic adenocarcinoma, colorectal cancer, bladder cancer, prostate cancer, cervical cancer, osteosarcoma, or soft tissue sarcomas and must have exhausted available standard-of-care therapies. Phase I is an open-label, single-arm dose escalation trial, with administration every 21 days. Dose escalation follows an accelerated titration design (ATD) transitioning to Bayesian optimal interval (BOIN) upon predefined toxicity thresholds. Backfill cohorts are planned in NSCLC and HNSCC to further evaluate the safety and efficacy profile at, or near, the maximum tolerated dose (MTD). Primary endpoints include safety and tolerability of TUB-030 as monotherapy, determination of the MTD and the recommended phase II doses; secondary endpoints assess pharmacokinetics, immunogenicity, and preliminary clinical activity using RECIST v1.1 criteria. Exploratory endpoints include analysis of circulating tumor DNA. In phase IIa, dose-optimization will evaluate two dose levels in select indications in order to identify the optimal dose for further development. Enrollment of approximately 130 patients across the US and Canada is planned, with dose escalation currently underway. This study investigates TUB-030, a novel 5T4 targeted ADC as a therapy for advanced/metastatic solid tumors. Clinical trial information: NCT06657222 .

Abstract Purpose: Recent advances have seen the development of targeted therapeutics against the receptor tyrosine kinase (RTK)/RAS/MAPK pathway, which, when aberrantly activated, drives the malignant transformation of many cancer indications. However, the efficacy of inhibitors targeting single molecules is dampened by pathway feedback activation and acquired drug resistance. We seek to evaluate the application of JAB-3312 (sitneprotafib), a potent inhibitor of SHP2, in RTK/RAS/MAPK pathway–targeted combination therapies. Furthermore, SHP2 plays a vital role in PD-1–mediated immunosuppression. The rational combination of JAB-3312 with PD-1 blocking therapies is also explored. Experimental Design: Biochemical and cellular assays were applied to evaluate the potency of JAB-3312 in SHP2 inhibition. Tumor cell lines and cell line– and patient-derived xenografts were used to test different combinations of JAB-3312 with KRASG12C, MEK, EGFR, and PD-1 inhibitors. Results: JAB-3312 produced potent in vitro inhibition of SHP2 activity and downstream ERK phosphorylation, with IC50 values of 1.44 nmol/L and 0.68 to 4.84 nmol/L, respectively. When used in combination, JAB-3312 significantly increased the antitumor activity of the KRASG12C inhibitor glecirasib in naïve and resistant models. The combination of JAB-3312 with MEK inhibitors significantly delayed RTK signaling reactivation and enhanced tumor growth inhibition in KRAS-mutated cancer models. The JAB-3312–osimertinib combination exhibited great efficacy in osimertinib-resistant non–small cell lung cancer models. Additionally, JAB-3312 enhanced the efficacy of PD-1 blockade therapies by promoting an antitumor microenvironment. Representative cases of patients who responded to the combination therapies from two ongoing clinical trials (NCT05288205 and NCT04720976) were reported. Conclusions: JAB-3312 in combination with RTK/RAS/MAPK or PD-1 blockade therapies is a promising strategy that warrants further clinical investigation.